Up-Front Tandem High-Dose Chemotherapy Compared With Standard Chemotherapy With Doxorubicin and Paclitaxel in Metastatic Breast Cancer: Resu
http://www.100md.com
《临床肿瘤学》
the Berlin Breast Cancer Research Group, Medizinische Klinik mit Schwerpunkt Onkologie und Hmatologie, Charite Campus Mitte, Humboldt Universitt zu Berlin, Berlin
Department of Oncology and Hematology, Franziskus Hospital, Bielefeld
Department of Oncology and Hematology, Westpfalz-Klinikum, Kaiserslautern
Department of Gynecology and Obstetrics, Universittsfrauenklinik, Ulm
Humaine Klinikum, Bad Saarow
Department for Intelligent Systems, University of Bremen, Bremen
Division of Oncology, Department of Internal Medicine, Medical University of Graz, Graz
Department of Oncology and Hematology, Landesklinik, Salzburg, Austria
ABSTRACT
PATIENTS AND METHODS: Patients without prior chemotherapy for metastatic disease were randomly assigned to standard combination therapy with doxorubicin and paclitaxel (AT) or double HDCT with cyclophosphamide, mitoxantrone, and etoposide followed by peripheral-blood stem-cell transplantation. HDCT was repeated after 6 weeks. Patients were stratified by menopausal and hormone-receptor status. The primary objective was to compare complete response (CR) rates.
RESULTS: A total of 93 patients were enrolled onto the trial. Intent-to-treat CR rates for patients randomized to HDCT and AT were 12.5% and 11.1%, respectively (P = .84). Objective response rates were 66.7% for patients in the high-dose group and 64.4% for patients in the AT arm (P = .82). In an intent-to-treat analysis, there were no significant differences between the two treatments in median time to progression (HDCT, 11.1 months; AT, 10.6 months; P = .67), duration of response (HDCT, 13.9 months; AT, 14.3 months; P = .98), and overall survival (HDCT, 26.9 months; AT, 23.4 months; P = .60). HDCT was associated with significantly more myelosuppression, infection, diarrhea, stomatitis, and nausea and vomiting, whereas patients treated with AT developed more neurotoxicity.
CONCLUSION: This trial failed to show a benefit for up-front tandem HDCT compared with standard combination therapy. HDCT was associated with more acute adverse effects.
INTRODUCTION
After these years in which HDCT was considered by many to represent standard of care for patients with high-risk primary or metastatic breast cancer, currently many physicians and most of the public believe that HDCT is both excessively toxic and ineffective. This extreme shift of opinion is based on the fact that the high expectations of patients and physicians alike have seemingly not been met to date.
In addition, the scientific misconduct investigation against Bezwoda et al,1 that revealed major irregularities, has further confused both public and medical society.2,3 Bezwoda et al had reported data of two randomized trials that showed a significant benefit of HDCT over conventional chemotherapy in women with primary and metastatic breast cancer. These results encouraged both breast cancer patients and physicians to use HDCT outside randomized trials. Since then, the articles have been retracted,1 but the public view and the medical debate remain influenced by the events.
Both the initial uncritical belief in the effects of HDCT and the more recent rejection of this modality have not helped to clearly define the role of HDCT. As of publication, data of five randomized trials that compare HDCT with nontransplantation strategies in metastatic breast cancer have become available.4,5,6,7,8 These studies used HDCT for consolidation after several courses of conventional induction chemotherapy. Although three of five trials were associated with a prolongation of progression-free survival, all trials failed to show a survival benefit for late intensification therapy. A recent meta-analysis of the randomized trials9 confirmed these results. Although HDCT was associated with an improved progression-free survival, there was no evidence of a benefit in overall survival.
One of the potential reasons for this failure might be that tumor cells develop drug resistance during conventional induction therapy, which late introduction of high-dose treatment cannot overcome. Accordingly, early intensification—high-dose treatment in an earlier, potentially more chemo-sensitive state—could theoretically provide a better approach.
This phase III study was therefore initiated to compare the efficacy and tolerability of up-front tandem HDCT and standard combination therapy in patients with metastatic breast cancer. Patients who had not received prior chemotherapy for metastatic disease were randomly assigned to conventional-dose combination therapy with doxorubicin and paclitaxel, or up-front double HDCT with cyclophosphamide, mitoxantrone, and etoposide followed by peripheral-blood stem-cell transplantation. The primary study end point was complete remission (CR) rates, with response rate, time to progression, overall survival, and quality of life evaluated as secondary end points.
PATIENTS AND METHODS
Objectives
The primary objective was to compare the CR rates of both treatments. Secondary objectives included comparison of objective response rates, time to progression (TTP), duration of response (DR), overall survival (OS), and safety.
Patient Eligibility
Patients aged 18 to 60 years with histologically confirmed metastatic breast cancer who had not received prior chemotherapy for metastatic disease were eligible for the study. Patients were required to have at least one bidimensionally measurable lesion that had not been irradiated.
All patients had to have adequate hematologic, renal, hepatic, and cardiac function (absolute neutrophil count [ANC] of > 1.5 x 109/L; platelets > 100 x 109/L; serum bilirubin ≤ 1.25x the laboratory upper normal limit [ULN], serum transaminase levels ≤ 1.25x ULN in patients without liver involvement or < 2.5x ULN in patients with liver metastases; serum creatinine level ≤ 1.25x ULN; left ventricular ejection fraction [LVEF] of at least 50%), an estimated life expectancy of at least 12 weeks, a negative pregnancy test, and appropriate contraception throughout the study (in premenopausal women only).
Written informed consent in accordance with institutional review board guidelines was required before patients were admitted to the study.
Patients were ineligible if they had received HDCT in the adjuvant setting. Any other adjuvant chemotherapy had to be concluded more than 6 months before enrollment onto the study.
Further exclusion criteria included brain metastases, bone metastases as the only site of measurable disease, a history of prior other malignancies, clinically significant pulmonary disease, a history of cardiac arrhythmias greater than grade II on the Lown scale, congestive heart failure, myocardial infarction within the 6 months before the study began, active infection, or other serious underlying medical or psychiatric conditions which would impair the patient's ability to give informed consent or receive protocol treatment. Pregnant or lactating women were ineligible.
Treatment Plan
Patients were randomized by study center in a 1:1 ratio to one of the two treatment groups, using a stratified random permuted block design (block size 4). Stratification was based on hormone-receptor status and menopausal status. Randomization was performed centrally at the coordinating study center, and was based on the order in which information on potential patients was received by fax.
Conventional Chemotherapy
The conventional chemotherapy (AT) consisted of intravenous (IV) infusions of doxorubicin (60 mg/m2 body surface area [BSA], IV infusion for 15 minutes) and paclitaxel (200 mg/m2 BSA, IV infusion for 3 hours). Treatment was repeated every 3 weeks for no more than six courses. Patients showing a partial response (PR) after six courses of AT received an additional three courses of single agent paclitaxel (200 mg/m2 BSA, IV infusion for 3 hours) if a complete response seemed achievable.
Premedication consisted of prednisolone 50 mg IV, dimetindenmaleate 10 mg IV, and cimetidine 300 mg IV administered at least 15 minutes before paclitaxel therapy. Standard antiemetic therapy was administered as needed, in compliance with the standards of the center. Recombinant granulocyte colony-stimulating factor (G-CSF; filgrastim 5 μg/kg, SC) was given on days 5 to 12, or until ANC > 1.5 x 109/L.
A new cycle of AT was started only if WBC was ≥ 2.0 x 109/L, and platelet count was ≥ 50 x 109/L. Doses were reduced by 25% if, on the day of treatment, WBC was 3.0 x 109/L to 3.5 x 109/L and/or platelet count was 70 x 109/L to 100 x 109/L. If WBC was 2.0 x 109/L to 3.0 x 109/L and/or platelet count was 50 x 109/L to 70 x 109/L, doses were reduced by 50%. Treatment was omitted in patients with a WBC less than 2.0 x 109/L and/or a platelet count less than 50 x 109/L.
In case of an elevation of serum bilirubin level to 1.5x ULN to 3.0x ULN, doses were reduced by 50%. Treatment was omitted in patients with serum bilirubin of more than 3.0 mg/dL.
HDCT
In the high-dose group, peripheral-blood progenitor cells (PBSC) were harvested before and after the first course of HDCT. For the first cycle, PBSCs were mobilized by IV infusion of cyclophosphamide (2 g/m2 BSA, IV infusion for 1 hour) and G-CSF at a dose of 10 μg/kg daily subcutaneously, starting the day after the application of cyclophosphamide. PBSC for the second HDCT cycle were mobilized by application of G-CSF at a dose of 10 μg/kg daily, starting 1 to 4 days after the first HDCT. A minimum of 2 x 106 CD34-positive cells per kilogram of body weight PBSCs were collected by leukocytapheresis and cryopreserved.
The HDCT regimen consisted of mitoxantrone (45 mg/m2 BSA, IV infusion for 1 hour), cyclophosphamide (2.4 g/m2 BSA for the first HDCT course, 4.4 g/m2 BSA for the second HDCT course, IV infusion for 1 hour), and etoposide (2.5 g/m2 BSA, IV infusion with 250 mg/h). The dose of mitoxantrone was reduced to 35 mg/m2 BSA in case of adjuvant anthracycline or anthracenedione pretreatment, or prior left-sided parasternal irradiation. PBSCs were infused approximately 24 hours after the last dose of chemotherapy. G-CSF was administered daily to stimulate hematopoetic recovery (ie, ANC > 1.0 x 109/L), starting 1 to 4 days after the last dose of chemotherapy. HDCT was repeated 6 weeks after the start of the first course.
Standard antiemetic therapy including 5-HT3 antagonists was administered in compliance with the standards of the center. IV uromitexan (1,000 mg/m2 BSA, IV infusion for 30 minutes) was given before cyclophosphamide infusion, and 6, 12, and 18 hours after cyclophosphamide. All patients received oral prophylactic antibiotics, including sulfamethoxazole (800 mg tid), trimethoprim (160 mg tid), colistin (200 mg tid), and amphothericin B (500 mg qid). Irradiated platelet transfusions were administered to maintain platelet count above 10 x 109/L, and irradiated leukocyte-depleted RBCs were given if hemoglobin was ≤ 8 g/dL.
General
Treatment consisted of six to nine courses of AT or two courses of HDCT, respectively, unless there was evidence of unacceptable toxicity, inadequate PBSC collection, disease progression, or patient request. Patients with grade 4 nonhematologic toxicities other than nausea, emesis, arthralgias, myalgias, or alopecia had to be withdrawn from the study.
In addition to the chemotherapy regimens patients received during the study, patients with bone metastases were treated concomitantly with IV pamidronate (90 mg as 2-hour infusion) every 3 weeks. Following completion of chemotherapy, hormone-receptor–positive patients with objective response or stable disease (SD) received tamoxifen or letrozole (in case of prior tamoxifen therapy only) until progression.
At progression, patients with CR to AT or HDCT were planned for cross-over HDCT or AT, respectively. Patients without a CR to first-line treatment went off study and received further treatment in compliance with the standards of the center.
Patient Evaluation and Follow-Up
Before entry onto the study, all patients underwent staging work-up including a complete medical history and physical examination, CBC, chemistry profile, urinalysis, screening for HIV infection and viral hepatitis, chest x-ray, abdominal ultrasound and/or a computed tomography, bone scintigraphy, and further imaging studies as necessary to document the extent of disease. In case of hot spots on the bone scan, conventional x-ray or nuclear magnetic resonance examination of the involved skeletal regions were required. All patients had an ECG and an echocardiogram before entry on the study.
Physical examination and serum chemistries were repeated before each cycle and CBC counts were obtained at least weekly while on therapy. Assessment of LVEF was performed before the second HDCT cycle, before courses 3, 5, and 7 of conventional therapy, respectively, and at the end of the study. Adverse events and toxicities were assessed at baseline and after every cycle. They were graded according to the National Cancer Institute Common Toxicity Criteria. All patients who received at least one course of therapy were assessable for toxicity.
Assessments of tumor response were performed after the second, fourth, sixth, and ninth courses of conventional therapy, and approximately 6 weeks after each HDCT cycle. Response was classified according to WHO criteria. A CR was defined as the disappearance of all clinical and radiographic evidence of cancer on two measurements separated by at least 4 weeks. A PR required a greater than 50% decrease in the sum of the product of the bidimensional parameters of all measurable disease documented by two measurements separated by at least 4 weeks. A decrease in size of tumor lesions of less than 50% or an increase of less than 25% was classified SD. An increase of ≥ 25% at any time or the occurrence of new lesions was considered to be progressive disease. If response was documented, imaging scans were performed no earlier than 4 weeks later to confirm the response.
Independent monitoring was performed to ensure the submission of data, the eligibility of the patients, compliance with the protocol, and source data verification.
Statistical Analysis
The study was originally planned with a two-step statistical design. The first part of the trial was designed to detect a 25% increase in CR rate with HDCT, with a power of 80% and a one-sided {alpha} error of 5%. In case of noninferiority of AT, the trial was planned to be extended to prove the equivalence of both treatments with a power of 80%, an {alpha} error of 5%, and a maximal difference of equivalence of 15%. Accordingly, the sample size was estimated at 220 patients and 140 patients per arm for the first and second phases, respectively, accounting for a total of 360 patients per treatment arm. Due to inadequate accrual, however, the steering committee decided in February 2002 to terminate the trial prematurely without completion of the first phase. Therefore, only exploratory data analyses were applied.
All analyses were primarily based on an intent-to-treat basis, including all randomized patients. Safety analyses were performed on all patients who received at least one course of therapy. The primary end point, CR rate, was defined as the percentage of patients in each treatment group who achieved a CR at any time. TTP was defined as the time from randomization until objective disease progression. DR was defined, for responding patients only, as the period of time from randomization to the first observation of disease progression. Survival was calculated from the date of randomization to the date of death for any reason.
The {chi}2 test and Fisher's exact test were used to compare CR rates, response rates, and toxicity. TTP, DR, OS and treatment-free interval were estimated using the Kaplan-Meier method, and compared using a two-sided log-rank test. Cox proportional hazards models were fitted in order to estimate hazard ratios and CIs. All analyses were performed using the SPSS version 11.0 software package (SPSS Inc, Chicago, IL). All P values were two-sided. Differences at P ≤ .05 were considered statistically significant.
RESULTS
Despite the premature termination of the trial, patient characteristics were well balanced between the two treatment arms (Table 1). All patients had disseminated disease, of which 87% of patients had visceral involvement and only 13% had disease confined to soft tissue and/or lymph nodes. Overall, 60% of patients had liver metastases, 42% had lung metastases, and 48% had bone metastases. Of the 93 patients, 28 patients (30%) had three or more involved metastatic sites. The extent of prior therapy was comparable in both arms. Fifty-four percent of patients had received prior adjuvant chemotherapy, including anthracyclines in 19 patients (20%).
Overall, 86 patients received treatment and were assessable for response. Whereas all randomized patients in the AT group received at least two cycles of therapy, seven patients in the HDCT group did not receive the planned treatment for the following reasons: two patients had to be withdrawn due to inadequate PBSC collection, one patient died of pulmonary embolism before initiation of treatment, two patients progressed rapidly before the first HDCT and had to be withdrawn due to low performance status, one patient was ineligible due to active viral hepatitis, and one patient refused to undergo HDCT and received conventional therapy outside the trial (Fig 1).
A total of 80 courses of HDCT and 273 courses of AT were administered. Most patients received the full planned therapy as the median number of courses was two in the HDCT group (range, 0 to 2) and six in the AT group (range, 2 to 9).
Among the 11 patients eligible for cross-over second-line therapy, only five received cross-over AT or HDCT, respectively. The other patients did not receive the planned treatment for the following reasons: two patients had symptomatic CNS metastases at progression, one patient had a relevant decrease in LVEF, one patient had to be withdrawn due to a reduced general performance status, one patient refused to undergo cross-over therapy, and one patient is still in remission.
Efficacy
Complete responses were documented in six (12.5%) of 48 randomized patients who received HDCT, and in five (11.1%) of 45 randomized patients who received AT (Table 2). Thirty-two patients (66.7%) in the HDCT group and 29 patients (64.4%) in the AT arm achieved an objective response. There were no statistical differences in CR rates and in objective response rates between the treatment groups. The median duration of response was similar in both arms (13.9 months for HDCT; 95% CI, 6.1 to 18.5; 14.3 months for AT; 95% CI, 6.1 to 22.5).
At a median follow-up of 52 months, tumor progression was documented in 78 (81% in the HDCT arm and 87% in the AT arm) of 93 patients, and 27 patients (29%) were alive. The 2- and 3-year progression-free survival rates were 26.7% and 8.9% for patients receiving HDCT, and 20.9% and 9.3% for patients treated with AT (2-year, P = .53; 3-year, P = .95). With an estimated median TTP of 11.1 months for the HDCT group (95% CI, 6.8 to 15.4) and 10.6 months for patients receiving AT (95% CI, 7.8 to 13.3; P = .67), there were no differences between both treatment arms (hazard ratio, 0.82; 95% CI, 0.52 to 1.29; Fig 2).
The 3-year survival rate among all 93 eligible patients was 19.6%, and the median survival was 26.9 months. There was no significant difference in OS between the two treatment groups (P = .60; Fig 3). The 3- and 4-year survival rates were 20.8% and 8.3% for patients in the HDCT group, and 18.2% and 13.6% for patients treated with AT (3-year, P = .75; 4-year, P = .41).
Toxicity
All 86 patients who received therapy were assessable for toxicity. As expected, the toxicity profiles of the two strategies were different. There was one treatment-related death in the HDCT arm, whereas no treatment-related deaths occurred in the conventional-dose arm.
Myelosuppression was significantly more pronounced after HDCT than after AT, with leukopenia and neutropenia being the most frequently encountered toxicities (P < .001; Table 3). The median time to hematopoetic recovery after HDCT (ie, ANC > 1.0 x 109/L) was 12 days.
Nonhematologic toxicities were also reflective of the expected toxicity profiles. The higher degree of myelosuppression in the HDCT arm was associated with an increased incidence of febrile neutropenia, compared with the AT arm (50% v 9% of patients; P < .001). One patient died from septicemia 36 days after the second course of HDCT.
Patients who underwent HDCT also had higher rates of mucositis, diarrhea, and vomiting, whereas peripheral neuropathy was more frequent in the AT arm. The incidence of renal, pulmonary, and hepatic toxicity was similar in the two groups.
Acute cardiac complications were infrequent in both arms. Subacute or late-onset cardiotoxicity was observed in three patients. In one patient, LVEF decreased to below 50% 3 months after the end of HDCT. The patient responded to standard therapy, resulting in an improvement of LVEF. Two other patients developed congestive heart failure during cross-over HDCT after six courses of first-line AT therapy. Symptoms improved in both patients under conventional therapy, though one patient had persistent congestive heart failure.
At the time of analysis, one patient had developed secondary acute myeloid leukemia. She had received one cycle of HDCT but had to be withdrawn because of inadequate stem-cell collection. Sixteen months after the end of therapy, secondary acute myeloid leukemia was diagnosed.
DISCUSSION
The primary study end point was CR rate. We recognize that this is no longer regarded as the optimal choice because of increasing evidence suggesting that progression-free or overall survival are more appropriate measures to determine the benefit of chemotherapy in metastatic breast cancer. However, at the time that this trial was designed, the decision was based on the assumption that patients who obtain a CR to chemotherapy might have a survival benefit. This hypothesis was, for example, supported by reports by the M.D. Anderson breast cancer group16 that showed 18.6% of patients with a CR to conventional-dose anthracycline–containing regimens were still in remission at 5 years, whereas less than 1% of patients with a PR or SD remained progression-free at the same time. Patients with a CR were also shown to have significantly longer progression-free and overall survival rates.
This hypothesis was, however, not supported by the present trial. With an estimated median TTP of 11.2 months for patients obtaining a CR after HDCT or AT (95% CI, 5.2 to 17.2) and 10.3 months for all other patients (95% CI, 8.4 to 12.2), there were no differences in progression-free survival with respect to the CR status (P = .37). Similar results were obtained for OS. Median OS was 27.7 months (95% CI, 9.5 to 45.9) for patients with a CR and 26.7 months (95% CI, 17.6 to 35.8) for all remaining patients (P = .79). Thus, the achievement of a CR was not associated with a benefit in terms of progression-free or overall survival.
The study was designed to have a high power to detect an increase of at least 25% in CR rates with HDCT. Because of the early termination of the trial, however, only exploratory data analyses were applied. Nonetheless, the reported data indicate that this HDCT regimen is unlikely to be associated with a substantial improvement in terms of response, TTP, or OS, when compared with conventional-dose chemotherapy. Results were similar for intent-to-treat and per protocol populations, though there was a nonsignificant trend in objective response in favor of HDCT. The fact that the protocol allowed patients in the conventional arm to receive HDCT at relapse is unlikely to have influenced the results, because only two patients were actually treated with HDCT as second-line therapy.
One of the reasons for the failure of HDCT might be that the major mechanisms of resistance in metastatic breast cancer cannot be totally overcome by augmenting the dose of currently available drugs. Most agents used for HDCT can undergo only modest intensification whereas more substantial increases in dose might be necessary. Furthermore, many of the drugs used for dose-intensive therapy have shown only modest therapeutic activity in conventional regimens, whereas some of the most active compounds like taxanes, anthracyclines, or vinorelbine have not been used for HDCT, because they exhibit significant and dose-limiting nonhematologic toxicity.
Despite the failure in the available trials, it remains possible that better selection of patients and relevant biologic predictors may identify subgroups of patients who would benefit from HDCT. In the adjuvant setting, for example, a significant interaction between HER2/neu status and treatment has been found, indicating that only patients with HER2/neu–negative disease might have a benefit from HDCT.17 In the metastatic setting, including this trial, subgroup analyses have been inconclusive because of the small size of the published trials. To overcome these limitations, larger-scale trials or meta-analyses are necessary. Larger trials could help to better define situations in which HDCT might be a valuable addition to current standard therapies. Such trials, however, seem to be difficult to carry out with respect to patient recruitment following the publication of several "negative" trials in this patient population.
Despite the fact that randomized trials failed to show an advantage in survival, HDCT is still a highly effective and relatively safe treatment option. HDCT is associated with substantially more acute adverse effects than standard-dose chemotherapy, but side effects are generally manageable. The treatment-related mortality after HDCT was 2.1%. Late toxicity was reported with cardiotoxicity in three patients (two patients in the AT arm, one patient in the HDCT group), but most likely seemed to be related to high cumulative doses of anthracycline and/or anthracenedione.
It is apparent that the high expectations that culminated in the belief that a single treatment with HDCT could offer the potential of cure in metastatic breast cancer have not been met. However, more realistic questions, such as whether the rate of patients going into long-term remission could be increased by HDCT, have not been answered sufficiently. No definite conclusion can currently be reached from the data of the randomized trials, especially with respect to the low number of patients enrolled and the limited statistical power. The trials might have ruled out a large benefit associated with HDCT, but smaller differences in outcome are not ruled out by these results.
In conclusion, the role of HDCT in metastatic breast cancer remains controversial. HDCT is a highly intensive approach that is still associated with substantial morbidity and treatment-related mortality. There has been no apparent survival benefit in previous trials with late-intensification HDCT. The presented trial also failed to show an advantage of up-front HDCT over standard combination therapy. Several issues, especially the approach of early intensification HDCT or the use of other cytotoxic compounds that are more active in the treatment of breast cancer, deserve further investigation. HDCT remains experimental and should not be considered standard for the treatment of metastatic breast cancer outside clinical trials until a clear benefit has been shown.
Appendix
Authors' Disclosures of Potential Conflicts of Interest
NOTES
Supported by Bristol-Myers Squibb (Munich, Germany), Amgen Pharma (Munich, Germany), and Wyeth Lederle, Germany.
Presented in part at the 38th Annual Meeting of the American Society of Clinical Oncology, Orlando, FL, May 18-21, 2002, at the 26th Annual San Antonio Breast Cancer Symposium, San Antonio, TX, December 3-6, 2003, and at the 40th Annual Meeting of the American Society of Clinical Oncology, New Orleans, LA, June 5-8, 2004.
Authors' disclosures of potential conflicts of interest are found at the end of this article.
REFERENCES
1. Bezwoda WR, Seymour L, Dansey RD: High-dose chemotherapy with hematopoietic rescue as primary treatment for metastatic breast cancer: A randomized trial. J Clin Oncol 13: 2483-2489, 1995; Retraction. J Clin Oncol 19:2973, 2001
2. Weiss RB, Rifkin RM, Stewart FM, et al: High-dose chemotherapy for high-risk primary breast cancer: An on-site review of the Bezwoda study. Lancet 355:999-1003, 2000
3. Weiss RB, Gill GG, Hudis CA: An on-site audit of the South African trial of high-dose chemotherapy for metastatic breast cancer and associated publications. J Clin Oncol 19:2771-2777, 2001
4. Stadtmauer EA, O'Neill A, Goldstein LJ, et al: Conventional-dose chemotherapy compared with high-dose chemotherapy plus autologous hematopoietic stem-cell transplantation for metastatic breast cancer. N Engl J Med 342:1069-1076, 2000
5. Crump M, Gluck S, Stewart D, et al: A randomized trial of high-dose chemotherapy with autologous peripheral blood stem cell support compared to standard therapy in women with metastatic breast cancer: A National Cancer Institute of Canada (NCIC) Clinical Trials Group Study. Proc Am Soc Clin Oncol 20:21a, 2001 (abstr 82)
6. Lotz J, Cure H, Janvier M, et al: Intensive therapy and autograft of hematopoetic stem cells in treating metastatic breast cancer: Results of the national programme PEGASE 04. Hematol Cell Ther 41:71-74, 1999
7. Biron P, Durand M, Roche H, et al: High dose thiotepa, cyclophosphamide (CPM) and stem cell transplantation after 4 FEC 100 compared with 4 FEC alone allowed better disease survival but the same overall survival in first line chemotherapy for metastatic breast cancer: Results of the PEGASE 03 French Protocols. Proc Am Soc Clin Oncol 21:42a, 2002 (abstr 167)
8. Crown J, Leyvraz S, Verril M, et al: Effect of tandem high-dose chemotherapy (HDC) on long-term complete remissions (LTCR) in metastatic breast cancer (MBC), compared to conventional-dose (CDC) in patients (pts) who were not selected in the basis of response to prior C: Mature results of the IBDIS-I. Proc Am Soc Clin Oncol 23:35s, 2004 (abstr 631)
9. Farquhar C, Basser R, Hetrick S, et al: High-dose chemotherapy and autologous bone marrow or stem cell transplantation versus conventional chemotherapy for women with metastatic breast cancer (Cochrane Review), in The Cochrane Library, Issue 4, 2002. Chichester, UK: John Wiley & Sons, Ltd
10. Lück HJ, Thomssen C, Untch M, et al: Multicentric phase III study in first line treatment of advanced metastatic breast cancer (ABC): Epirubicin/paclitaxel (ET) vs epirubicin/cyclophosphamide (EC)—A study of the Ago Breast Cancer Group. Proc Am Soc Clin Oncol 19:73a, 2000 (abstr 280)
11. Biganzoli L, Cufer T, Bruning P, et al: Doxorubicin and paclitaxel versus doxorubicin and cyclophosphamide as first-line chemotherapy in metastatic breast cancer: EORTC 10961. J Clin Oncol 20:3114-3121, 2002
12. Jassem J, Pienkowski T, Pluzanska A, et al: Doxorubicin and paclitaxel versus fluorouracil, doxorubicin, and cyclophosphamide as first-line therapy for women with metastatic breast cancer: Final results of a randomized phase III multicenter trial. J Clin Oncol 19:1707-1715, 2001
13. Nabholtz JA, Falkson C, Campos D, et al: Docetaxel and doxorubicin compared with doxorubicin and cyclophosphamide as first line chemotherapy for metastatic breast cancer: Results of a randomized, multicenter, phase III trial. J Clin Oncol 21:968-975, 2003
14. Tubiana-Hulin M, Bonneterre J, Bougnoux P, et al: Better survival with epirubicin-paclitaxel (ET) combination as first-line chemotherapy in patients with metastatic breast cancer (MBC): Final results of a phase II randomized study. Proc Am Soc Clin Oncol 22:46, 2003 (abstr 182)
15. Mackay JR, Paterson A, Dirix L, et al: Final results of the phase III randomized trial comparing docetaxel (T), doxorubicin (A) and cyclophosphamide (C) to FAC as first line chemotherapy (CT) for patients (pts) with metastatic breast cancer (MBC). Proc Am Soc Clin Oncol 21:35a, 2002 (abstr 137)
16. Greenberg PAC, Hortobagyi G, Smith T, et al: Long-term follow-up of patients with complete remission following combination chemotherapy for metastatic breast cancer. J Clin Oncol 14:2197-2205, 1996
17. Rodenhuis S, Bontenbal M, Robert NJ, et al: High-dose chemotherapy with hematopoetic stem-cell rescue for high-risk breast cancer. N Engl J Med 349:7-16, 2003(Peter Schmid, Walter Schi)
Department of Oncology and Hematology, Franziskus Hospital, Bielefeld
Department of Oncology and Hematology, Westpfalz-Klinikum, Kaiserslautern
Department of Gynecology and Obstetrics, Universittsfrauenklinik, Ulm
Humaine Klinikum, Bad Saarow
Department for Intelligent Systems, University of Bremen, Bremen
Division of Oncology, Department of Internal Medicine, Medical University of Graz, Graz
Department of Oncology and Hematology, Landesklinik, Salzburg, Austria
ABSTRACT
PATIENTS AND METHODS: Patients without prior chemotherapy for metastatic disease were randomly assigned to standard combination therapy with doxorubicin and paclitaxel (AT) or double HDCT with cyclophosphamide, mitoxantrone, and etoposide followed by peripheral-blood stem-cell transplantation. HDCT was repeated after 6 weeks. Patients were stratified by menopausal and hormone-receptor status. The primary objective was to compare complete response (CR) rates.
RESULTS: A total of 93 patients were enrolled onto the trial. Intent-to-treat CR rates for patients randomized to HDCT and AT were 12.5% and 11.1%, respectively (P = .84). Objective response rates were 66.7% for patients in the high-dose group and 64.4% for patients in the AT arm (P = .82). In an intent-to-treat analysis, there were no significant differences between the two treatments in median time to progression (HDCT, 11.1 months; AT, 10.6 months; P = .67), duration of response (HDCT, 13.9 months; AT, 14.3 months; P = .98), and overall survival (HDCT, 26.9 months; AT, 23.4 months; P = .60). HDCT was associated with significantly more myelosuppression, infection, diarrhea, stomatitis, and nausea and vomiting, whereas patients treated with AT developed more neurotoxicity.
CONCLUSION: This trial failed to show a benefit for up-front tandem HDCT compared with standard combination therapy. HDCT was associated with more acute adverse effects.
INTRODUCTION
After these years in which HDCT was considered by many to represent standard of care for patients with high-risk primary or metastatic breast cancer, currently many physicians and most of the public believe that HDCT is both excessively toxic and ineffective. This extreme shift of opinion is based on the fact that the high expectations of patients and physicians alike have seemingly not been met to date.
In addition, the scientific misconduct investigation against Bezwoda et al,1 that revealed major irregularities, has further confused both public and medical society.2,3 Bezwoda et al had reported data of two randomized trials that showed a significant benefit of HDCT over conventional chemotherapy in women with primary and metastatic breast cancer. These results encouraged both breast cancer patients and physicians to use HDCT outside randomized trials. Since then, the articles have been retracted,1 but the public view and the medical debate remain influenced by the events.
Both the initial uncritical belief in the effects of HDCT and the more recent rejection of this modality have not helped to clearly define the role of HDCT. As of publication, data of five randomized trials that compare HDCT with nontransplantation strategies in metastatic breast cancer have become available.4,5,6,7,8 These studies used HDCT for consolidation after several courses of conventional induction chemotherapy. Although three of five trials were associated with a prolongation of progression-free survival, all trials failed to show a survival benefit for late intensification therapy. A recent meta-analysis of the randomized trials9 confirmed these results. Although HDCT was associated with an improved progression-free survival, there was no evidence of a benefit in overall survival.
One of the potential reasons for this failure might be that tumor cells develop drug resistance during conventional induction therapy, which late introduction of high-dose treatment cannot overcome. Accordingly, early intensification—high-dose treatment in an earlier, potentially more chemo-sensitive state—could theoretically provide a better approach.
This phase III study was therefore initiated to compare the efficacy and tolerability of up-front tandem HDCT and standard combination therapy in patients with metastatic breast cancer. Patients who had not received prior chemotherapy for metastatic disease were randomly assigned to conventional-dose combination therapy with doxorubicin and paclitaxel, or up-front double HDCT with cyclophosphamide, mitoxantrone, and etoposide followed by peripheral-blood stem-cell transplantation. The primary study end point was complete remission (CR) rates, with response rate, time to progression, overall survival, and quality of life evaluated as secondary end points.
PATIENTS AND METHODS
Objectives
The primary objective was to compare the CR rates of both treatments. Secondary objectives included comparison of objective response rates, time to progression (TTP), duration of response (DR), overall survival (OS), and safety.
Patient Eligibility
Patients aged 18 to 60 years with histologically confirmed metastatic breast cancer who had not received prior chemotherapy for metastatic disease were eligible for the study. Patients were required to have at least one bidimensionally measurable lesion that had not been irradiated.
All patients had to have adequate hematologic, renal, hepatic, and cardiac function (absolute neutrophil count [ANC] of > 1.5 x 109/L; platelets > 100 x 109/L; serum bilirubin ≤ 1.25x the laboratory upper normal limit [ULN], serum transaminase levels ≤ 1.25x ULN in patients without liver involvement or < 2.5x ULN in patients with liver metastases; serum creatinine level ≤ 1.25x ULN; left ventricular ejection fraction [LVEF] of at least 50%), an estimated life expectancy of at least 12 weeks, a negative pregnancy test, and appropriate contraception throughout the study (in premenopausal women only).
Written informed consent in accordance with institutional review board guidelines was required before patients were admitted to the study.
Patients were ineligible if they had received HDCT in the adjuvant setting. Any other adjuvant chemotherapy had to be concluded more than 6 months before enrollment onto the study.
Further exclusion criteria included brain metastases, bone metastases as the only site of measurable disease, a history of prior other malignancies, clinically significant pulmonary disease, a history of cardiac arrhythmias greater than grade II on the Lown scale, congestive heart failure, myocardial infarction within the 6 months before the study began, active infection, or other serious underlying medical or psychiatric conditions which would impair the patient's ability to give informed consent or receive protocol treatment. Pregnant or lactating women were ineligible.
Treatment Plan
Patients were randomized by study center in a 1:1 ratio to one of the two treatment groups, using a stratified random permuted block design (block size 4). Stratification was based on hormone-receptor status and menopausal status. Randomization was performed centrally at the coordinating study center, and was based on the order in which information on potential patients was received by fax.
Conventional Chemotherapy
The conventional chemotherapy (AT) consisted of intravenous (IV) infusions of doxorubicin (60 mg/m2 body surface area [BSA], IV infusion for 15 minutes) and paclitaxel (200 mg/m2 BSA, IV infusion for 3 hours). Treatment was repeated every 3 weeks for no more than six courses. Patients showing a partial response (PR) after six courses of AT received an additional three courses of single agent paclitaxel (200 mg/m2 BSA, IV infusion for 3 hours) if a complete response seemed achievable.
Premedication consisted of prednisolone 50 mg IV, dimetindenmaleate 10 mg IV, and cimetidine 300 mg IV administered at least 15 minutes before paclitaxel therapy. Standard antiemetic therapy was administered as needed, in compliance with the standards of the center. Recombinant granulocyte colony-stimulating factor (G-CSF; filgrastim 5 μg/kg, SC) was given on days 5 to 12, or until ANC > 1.5 x 109/L.
A new cycle of AT was started only if WBC was ≥ 2.0 x 109/L, and platelet count was ≥ 50 x 109/L. Doses were reduced by 25% if, on the day of treatment, WBC was 3.0 x 109/L to 3.5 x 109/L and/or platelet count was 70 x 109/L to 100 x 109/L. If WBC was 2.0 x 109/L to 3.0 x 109/L and/or platelet count was 50 x 109/L to 70 x 109/L, doses were reduced by 50%. Treatment was omitted in patients with a WBC less than 2.0 x 109/L and/or a platelet count less than 50 x 109/L.
In case of an elevation of serum bilirubin level to 1.5x ULN to 3.0x ULN, doses were reduced by 50%. Treatment was omitted in patients with serum bilirubin of more than 3.0 mg/dL.
HDCT
In the high-dose group, peripheral-blood progenitor cells (PBSC) were harvested before and after the first course of HDCT. For the first cycle, PBSCs were mobilized by IV infusion of cyclophosphamide (2 g/m2 BSA, IV infusion for 1 hour) and G-CSF at a dose of 10 μg/kg daily subcutaneously, starting the day after the application of cyclophosphamide. PBSC for the second HDCT cycle were mobilized by application of G-CSF at a dose of 10 μg/kg daily, starting 1 to 4 days after the first HDCT. A minimum of 2 x 106 CD34-positive cells per kilogram of body weight PBSCs were collected by leukocytapheresis and cryopreserved.
The HDCT regimen consisted of mitoxantrone (45 mg/m2 BSA, IV infusion for 1 hour), cyclophosphamide (2.4 g/m2 BSA for the first HDCT course, 4.4 g/m2 BSA for the second HDCT course, IV infusion for 1 hour), and etoposide (2.5 g/m2 BSA, IV infusion with 250 mg/h). The dose of mitoxantrone was reduced to 35 mg/m2 BSA in case of adjuvant anthracycline or anthracenedione pretreatment, or prior left-sided parasternal irradiation. PBSCs were infused approximately 24 hours after the last dose of chemotherapy. G-CSF was administered daily to stimulate hematopoetic recovery (ie, ANC > 1.0 x 109/L), starting 1 to 4 days after the last dose of chemotherapy. HDCT was repeated 6 weeks after the start of the first course.
Standard antiemetic therapy including 5-HT3 antagonists was administered in compliance with the standards of the center. IV uromitexan (1,000 mg/m2 BSA, IV infusion for 30 minutes) was given before cyclophosphamide infusion, and 6, 12, and 18 hours after cyclophosphamide. All patients received oral prophylactic antibiotics, including sulfamethoxazole (800 mg tid), trimethoprim (160 mg tid), colistin (200 mg tid), and amphothericin B (500 mg qid). Irradiated platelet transfusions were administered to maintain platelet count above 10 x 109/L, and irradiated leukocyte-depleted RBCs were given if hemoglobin was ≤ 8 g/dL.
General
Treatment consisted of six to nine courses of AT or two courses of HDCT, respectively, unless there was evidence of unacceptable toxicity, inadequate PBSC collection, disease progression, or patient request. Patients with grade 4 nonhematologic toxicities other than nausea, emesis, arthralgias, myalgias, or alopecia had to be withdrawn from the study.
In addition to the chemotherapy regimens patients received during the study, patients with bone metastases were treated concomitantly with IV pamidronate (90 mg as 2-hour infusion) every 3 weeks. Following completion of chemotherapy, hormone-receptor–positive patients with objective response or stable disease (SD) received tamoxifen or letrozole (in case of prior tamoxifen therapy only) until progression.
At progression, patients with CR to AT or HDCT were planned for cross-over HDCT or AT, respectively. Patients without a CR to first-line treatment went off study and received further treatment in compliance with the standards of the center.
Patient Evaluation and Follow-Up
Before entry onto the study, all patients underwent staging work-up including a complete medical history and physical examination, CBC, chemistry profile, urinalysis, screening for HIV infection and viral hepatitis, chest x-ray, abdominal ultrasound and/or a computed tomography, bone scintigraphy, and further imaging studies as necessary to document the extent of disease. In case of hot spots on the bone scan, conventional x-ray or nuclear magnetic resonance examination of the involved skeletal regions were required. All patients had an ECG and an echocardiogram before entry on the study.
Physical examination and serum chemistries were repeated before each cycle and CBC counts were obtained at least weekly while on therapy. Assessment of LVEF was performed before the second HDCT cycle, before courses 3, 5, and 7 of conventional therapy, respectively, and at the end of the study. Adverse events and toxicities were assessed at baseline and after every cycle. They were graded according to the National Cancer Institute Common Toxicity Criteria. All patients who received at least one course of therapy were assessable for toxicity.
Assessments of tumor response were performed after the second, fourth, sixth, and ninth courses of conventional therapy, and approximately 6 weeks after each HDCT cycle. Response was classified according to WHO criteria. A CR was defined as the disappearance of all clinical and radiographic evidence of cancer on two measurements separated by at least 4 weeks. A PR required a greater than 50% decrease in the sum of the product of the bidimensional parameters of all measurable disease documented by two measurements separated by at least 4 weeks. A decrease in size of tumor lesions of less than 50% or an increase of less than 25% was classified SD. An increase of ≥ 25% at any time or the occurrence of new lesions was considered to be progressive disease. If response was documented, imaging scans were performed no earlier than 4 weeks later to confirm the response.
Independent monitoring was performed to ensure the submission of data, the eligibility of the patients, compliance with the protocol, and source data verification.
Statistical Analysis
The study was originally planned with a two-step statistical design. The first part of the trial was designed to detect a 25% increase in CR rate with HDCT, with a power of 80% and a one-sided {alpha} error of 5%. In case of noninferiority of AT, the trial was planned to be extended to prove the equivalence of both treatments with a power of 80%, an {alpha} error of 5%, and a maximal difference of equivalence of 15%. Accordingly, the sample size was estimated at 220 patients and 140 patients per arm for the first and second phases, respectively, accounting for a total of 360 patients per treatment arm. Due to inadequate accrual, however, the steering committee decided in February 2002 to terminate the trial prematurely without completion of the first phase. Therefore, only exploratory data analyses were applied.
All analyses were primarily based on an intent-to-treat basis, including all randomized patients. Safety analyses were performed on all patients who received at least one course of therapy. The primary end point, CR rate, was defined as the percentage of patients in each treatment group who achieved a CR at any time. TTP was defined as the time from randomization until objective disease progression. DR was defined, for responding patients only, as the period of time from randomization to the first observation of disease progression. Survival was calculated from the date of randomization to the date of death for any reason.
The {chi}2 test and Fisher's exact test were used to compare CR rates, response rates, and toxicity. TTP, DR, OS and treatment-free interval were estimated using the Kaplan-Meier method, and compared using a two-sided log-rank test. Cox proportional hazards models were fitted in order to estimate hazard ratios and CIs. All analyses were performed using the SPSS version 11.0 software package (SPSS Inc, Chicago, IL). All P values were two-sided. Differences at P ≤ .05 were considered statistically significant.
RESULTS
Despite the premature termination of the trial, patient characteristics were well balanced between the two treatment arms (Table 1). All patients had disseminated disease, of which 87% of patients had visceral involvement and only 13% had disease confined to soft tissue and/or lymph nodes. Overall, 60% of patients had liver metastases, 42% had lung metastases, and 48% had bone metastases. Of the 93 patients, 28 patients (30%) had three or more involved metastatic sites. The extent of prior therapy was comparable in both arms. Fifty-four percent of patients had received prior adjuvant chemotherapy, including anthracyclines in 19 patients (20%).
Overall, 86 patients received treatment and were assessable for response. Whereas all randomized patients in the AT group received at least two cycles of therapy, seven patients in the HDCT group did not receive the planned treatment for the following reasons: two patients had to be withdrawn due to inadequate PBSC collection, one patient died of pulmonary embolism before initiation of treatment, two patients progressed rapidly before the first HDCT and had to be withdrawn due to low performance status, one patient was ineligible due to active viral hepatitis, and one patient refused to undergo HDCT and received conventional therapy outside the trial (Fig 1).
A total of 80 courses of HDCT and 273 courses of AT were administered. Most patients received the full planned therapy as the median number of courses was two in the HDCT group (range, 0 to 2) and six in the AT group (range, 2 to 9).
Among the 11 patients eligible for cross-over second-line therapy, only five received cross-over AT or HDCT, respectively. The other patients did not receive the planned treatment for the following reasons: two patients had symptomatic CNS metastases at progression, one patient had a relevant decrease in LVEF, one patient had to be withdrawn due to a reduced general performance status, one patient refused to undergo cross-over therapy, and one patient is still in remission.
Efficacy
Complete responses were documented in six (12.5%) of 48 randomized patients who received HDCT, and in five (11.1%) of 45 randomized patients who received AT (Table 2). Thirty-two patients (66.7%) in the HDCT group and 29 patients (64.4%) in the AT arm achieved an objective response. There were no statistical differences in CR rates and in objective response rates between the treatment groups. The median duration of response was similar in both arms (13.9 months for HDCT; 95% CI, 6.1 to 18.5; 14.3 months for AT; 95% CI, 6.1 to 22.5).
At a median follow-up of 52 months, tumor progression was documented in 78 (81% in the HDCT arm and 87% in the AT arm) of 93 patients, and 27 patients (29%) were alive. The 2- and 3-year progression-free survival rates were 26.7% and 8.9% for patients receiving HDCT, and 20.9% and 9.3% for patients treated with AT (2-year, P = .53; 3-year, P = .95). With an estimated median TTP of 11.1 months for the HDCT group (95% CI, 6.8 to 15.4) and 10.6 months for patients receiving AT (95% CI, 7.8 to 13.3; P = .67), there were no differences between both treatment arms (hazard ratio, 0.82; 95% CI, 0.52 to 1.29; Fig 2).
The 3-year survival rate among all 93 eligible patients was 19.6%, and the median survival was 26.9 months. There was no significant difference in OS between the two treatment groups (P = .60; Fig 3). The 3- and 4-year survival rates were 20.8% and 8.3% for patients in the HDCT group, and 18.2% and 13.6% for patients treated with AT (3-year, P = .75; 4-year, P = .41).
Toxicity
All 86 patients who received therapy were assessable for toxicity. As expected, the toxicity profiles of the two strategies were different. There was one treatment-related death in the HDCT arm, whereas no treatment-related deaths occurred in the conventional-dose arm.
Myelosuppression was significantly more pronounced after HDCT than after AT, with leukopenia and neutropenia being the most frequently encountered toxicities (P < .001; Table 3). The median time to hematopoetic recovery after HDCT (ie, ANC > 1.0 x 109/L) was 12 days.
Nonhematologic toxicities were also reflective of the expected toxicity profiles. The higher degree of myelosuppression in the HDCT arm was associated with an increased incidence of febrile neutropenia, compared with the AT arm (50% v 9% of patients; P < .001). One patient died from septicemia 36 days after the second course of HDCT.
Patients who underwent HDCT also had higher rates of mucositis, diarrhea, and vomiting, whereas peripheral neuropathy was more frequent in the AT arm. The incidence of renal, pulmonary, and hepatic toxicity was similar in the two groups.
Acute cardiac complications were infrequent in both arms. Subacute or late-onset cardiotoxicity was observed in three patients. In one patient, LVEF decreased to below 50% 3 months after the end of HDCT. The patient responded to standard therapy, resulting in an improvement of LVEF. Two other patients developed congestive heart failure during cross-over HDCT after six courses of first-line AT therapy. Symptoms improved in both patients under conventional therapy, though one patient had persistent congestive heart failure.
At the time of analysis, one patient had developed secondary acute myeloid leukemia. She had received one cycle of HDCT but had to be withdrawn because of inadequate stem-cell collection. Sixteen months after the end of therapy, secondary acute myeloid leukemia was diagnosed.
DISCUSSION
The primary study end point was CR rate. We recognize that this is no longer regarded as the optimal choice because of increasing evidence suggesting that progression-free or overall survival are more appropriate measures to determine the benefit of chemotherapy in metastatic breast cancer. However, at the time that this trial was designed, the decision was based on the assumption that patients who obtain a CR to chemotherapy might have a survival benefit. This hypothesis was, for example, supported by reports by the M.D. Anderson breast cancer group16 that showed 18.6% of patients with a CR to conventional-dose anthracycline–containing regimens were still in remission at 5 years, whereas less than 1% of patients with a PR or SD remained progression-free at the same time. Patients with a CR were also shown to have significantly longer progression-free and overall survival rates.
This hypothesis was, however, not supported by the present trial. With an estimated median TTP of 11.2 months for patients obtaining a CR after HDCT or AT (95% CI, 5.2 to 17.2) and 10.3 months for all other patients (95% CI, 8.4 to 12.2), there were no differences in progression-free survival with respect to the CR status (P = .37). Similar results were obtained for OS. Median OS was 27.7 months (95% CI, 9.5 to 45.9) for patients with a CR and 26.7 months (95% CI, 17.6 to 35.8) for all remaining patients (P = .79). Thus, the achievement of a CR was not associated with a benefit in terms of progression-free or overall survival.
The study was designed to have a high power to detect an increase of at least 25% in CR rates with HDCT. Because of the early termination of the trial, however, only exploratory data analyses were applied. Nonetheless, the reported data indicate that this HDCT regimen is unlikely to be associated with a substantial improvement in terms of response, TTP, or OS, when compared with conventional-dose chemotherapy. Results were similar for intent-to-treat and per protocol populations, though there was a nonsignificant trend in objective response in favor of HDCT. The fact that the protocol allowed patients in the conventional arm to receive HDCT at relapse is unlikely to have influenced the results, because only two patients were actually treated with HDCT as second-line therapy.
One of the reasons for the failure of HDCT might be that the major mechanisms of resistance in metastatic breast cancer cannot be totally overcome by augmenting the dose of currently available drugs. Most agents used for HDCT can undergo only modest intensification whereas more substantial increases in dose might be necessary. Furthermore, many of the drugs used for dose-intensive therapy have shown only modest therapeutic activity in conventional regimens, whereas some of the most active compounds like taxanes, anthracyclines, or vinorelbine have not been used for HDCT, because they exhibit significant and dose-limiting nonhematologic toxicity.
Despite the failure in the available trials, it remains possible that better selection of patients and relevant biologic predictors may identify subgroups of patients who would benefit from HDCT. In the adjuvant setting, for example, a significant interaction between HER2/neu status and treatment has been found, indicating that only patients with HER2/neu–negative disease might have a benefit from HDCT.17 In the metastatic setting, including this trial, subgroup analyses have been inconclusive because of the small size of the published trials. To overcome these limitations, larger-scale trials or meta-analyses are necessary. Larger trials could help to better define situations in which HDCT might be a valuable addition to current standard therapies. Such trials, however, seem to be difficult to carry out with respect to patient recruitment following the publication of several "negative" trials in this patient population.
Despite the fact that randomized trials failed to show an advantage in survival, HDCT is still a highly effective and relatively safe treatment option. HDCT is associated with substantially more acute adverse effects than standard-dose chemotherapy, but side effects are generally manageable. The treatment-related mortality after HDCT was 2.1%. Late toxicity was reported with cardiotoxicity in three patients (two patients in the AT arm, one patient in the HDCT group), but most likely seemed to be related to high cumulative doses of anthracycline and/or anthracenedione.
It is apparent that the high expectations that culminated in the belief that a single treatment with HDCT could offer the potential of cure in metastatic breast cancer have not been met. However, more realistic questions, such as whether the rate of patients going into long-term remission could be increased by HDCT, have not been answered sufficiently. No definite conclusion can currently be reached from the data of the randomized trials, especially with respect to the low number of patients enrolled and the limited statistical power. The trials might have ruled out a large benefit associated with HDCT, but smaller differences in outcome are not ruled out by these results.
In conclusion, the role of HDCT in metastatic breast cancer remains controversial. HDCT is a highly intensive approach that is still associated with substantial morbidity and treatment-related mortality. There has been no apparent survival benefit in previous trials with late-intensification HDCT. The presented trial also failed to show an advantage of up-front HDCT over standard combination therapy. Several issues, especially the approach of early intensification HDCT or the use of other cytotoxic compounds that are more active in the treatment of breast cancer, deserve further investigation. HDCT remains experimental and should not be considered standard for the treatment of metastatic breast cancer outside clinical trials until a clear benefit has been shown.
Appendix
Authors' Disclosures of Potential Conflicts of Interest
NOTES
Supported by Bristol-Myers Squibb (Munich, Germany), Amgen Pharma (Munich, Germany), and Wyeth Lederle, Germany.
Presented in part at the 38th Annual Meeting of the American Society of Clinical Oncology, Orlando, FL, May 18-21, 2002, at the 26th Annual San Antonio Breast Cancer Symposium, San Antonio, TX, December 3-6, 2003, and at the 40th Annual Meeting of the American Society of Clinical Oncology, New Orleans, LA, June 5-8, 2004.
Authors' disclosures of potential conflicts of interest are found at the end of this article.
REFERENCES
1. Bezwoda WR, Seymour L, Dansey RD: High-dose chemotherapy with hematopoietic rescue as primary treatment for metastatic breast cancer: A randomized trial. J Clin Oncol 13: 2483-2489, 1995; Retraction. J Clin Oncol 19:2973, 2001
2. Weiss RB, Rifkin RM, Stewart FM, et al: High-dose chemotherapy for high-risk primary breast cancer: An on-site review of the Bezwoda study. Lancet 355:999-1003, 2000
3. Weiss RB, Gill GG, Hudis CA: An on-site audit of the South African trial of high-dose chemotherapy for metastatic breast cancer and associated publications. J Clin Oncol 19:2771-2777, 2001
4. Stadtmauer EA, O'Neill A, Goldstein LJ, et al: Conventional-dose chemotherapy compared with high-dose chemotherapy plus autologous hematopoietic stem-cell transplantation for metastatic breast cancer. N Engl J Med 342:1069-1076, 2000
5. Crump M, Gluck S, Stewart D, et al: A randomized trial of high-dose chemotherapy with autologous peripheral blood stem cell support compared to standard therapy in women with metastatic breast cancer: A National Cancer Institute of Canada (NCIC) Clinical Trials Group Study. Proc Am Soc Clin Oncol 20:21a, 2001 (abstr 82)
6. Lotz J, Cure H, Janvier M, et al: Intensive therapy and autograft of hematopoetic stem cells in treating metastatic breast cancer: Results of the national programme PEGASE 04. Hematol Cell Ther 41:71-74, 1999
7. Biron P, Durand M, Roche H, et al: High dose thiotepa, cyclophosphamide (CPM) and stem cell transplantation after 4 FEC 100 compared with 4 FEC alone allowed better disease survival but the same overall survival in first line chemotherapy for metastatic breast cancer: Results of the PEGASE 03 French Protocols. Proc Am Soc Clin Oncol 21:42a, 2002 (abstr 167)
8. Crown J, Leyvraz S, Verril M, et al: Effect of tandem high-dose chemotherapy (HDC) on long-term complete remissions (LTCR) in metastatic breast cancer (MBC), compared to conventional-dose (CDC) in patients (pts) who were not selected in the basis of response to prior C: Mature results of the IBDIS-I. Proc Am Soc Clin Oncol 23:35s, 2004 (abstr 631)
9. Farquhar C, Basser R, Hetrick S, et al: High-dose chemotherapy and autologous bone marrow or stem cell transplantation versus conventional chemotherapy for women with metastatic breast cancer (Cochrane Review), in The Cochrane Library, Issue 4, 2002. Chichester, UK: John Wiley & Sons, Ltd
10. Lück HJ, Thomssen C, Untch M, et al: Multicentric phase III study in first line treatment of advanced metastatic breast cancer (ABC): Epirubicin/paclitaxel (ET) vs epirubicin/cyclophosphamide (EC)—A study of the Ago Breast Cancer Group. Proc Am Soc Clin Oncol 19:73a, 2000 (abstr 280)
11. Biganzoli L, Cufer T, Bruning P, et al: Doxorubicin and paclitaxel versus doxorubicin and cyclophosphamide as first-line chemotherapy in metastatic breast cancer: EORTC 10961. J Clin Oncol 20:3114-3121, 2002
12. Jassem J, Pienkowski T, Pluzanska A, et al: Doxorubicin and paclitaxel versus fluorouracil, doxorubicin, and cyclophosphamide as first-line therapy for women with metastatic breast cancer: Final results of a randomized phase III multicenter trial. J Clin Oncol 19:1707-1715, 2001
13. Nabholtz JA, Falkson C, Campos D, et al: Docetaxel and doxorubicin compared with doxorubicin and cyclophosphamide as first line chemotherapy for metastatic breast cancer: Results of a randomized, multicenter, phase III trial. J Clin Oncol 21:968-975, 2003
14. Tubiana-Hulin M, Bonneterre J, Bougnoux P, et al: Better survival with epirubicin-paclitaxel (ET) combination as first-line chemotherapy in patients with metastatic breast cancer (MBC): Final results of a phase II randomized study. Proc Am Soc Clin Oncol 22:46, 2003 (abstr 182)
15. Mackay JR, Paterson A, Dirix L, et al: Final results of the phase III randomized trial comparing docetaxel (T), doxorubicin (A) and cyclophosphamide (C) to FAC as first line chemotherapy (CT) for patients (pts) with metastatic breast cancer (MBC). Proc Am Soc Clin Oncol 21:35a, 2002 (abstr 137)
16. Greenberg PAC, Hortobagyi G, Smith T, et al: Long-term follow-up of patients with complete remission following combination chemotherapy for metastatic breast cancer. J Clin Oncol 14:2197-2205, 1996
17. Rodenhuis S, Bontenbal M, Robert NJ, et al: High-dose chemotherapy with hematopoetic stem-cell rescue for high-risk breast cancer. N Engl J Med 349:7-16, 2003(Peter Schmid, Walter Schi)